Data from clinical studies and the World Trade Center (WTC) Health Registry have revealed increases in cardiovascular (CV) diseases among first responders (FR) who were present at Ground Zero over the initial 72 hr. after the collapse. It has yet not been established that WTC dusts can act as causative agents to alter CV health. Even if WTC dusts were not direct inducers of CV changes in the FR, it was possible they might have caused damage in situ that modulated the impact of another co-pollutant with a known ability to impact the CV system - and was also present at high levels in Ground Zero air - diesel exhaust particles (DEP; from trucks, generators, cranes). Our previous analyses showed that rats exposed to the alkaline WTC dusts [using exposures/levels mimicking FR mouth-breathing] led to persistent reductions in airway ciliated cell numbers and clearance of the WTC dust itself. Accordingly, we hypothesize that entrained WTC dusts may have acted as direct inducers of CV damage and/or caused enhanced DEP-induced CV injuries as a result of increased pulmonary retention of this co-pollutant. As FR models, rats will be exposed on 2 consecutive days (2 hr./d, by intratracheal inhalation) to WTC dust (collected on-site 9/12 & 9/13), DEP, or the two pollutants in combination, and examined for changes in their CV structures/functions (latter to include heart rate [and variability], left ventricular stroke volume, cardiac output, ejection fraction, and ex vivo measures of aorta/mesenteric artery vasoconstrictor responses) at multiple timepoints over 1 yr thereafter. Exposures will use dust/DEP levels extrapolated from those experienced over 4-hr periods by `reference FR'. Three inter-related Specific Aims are proposed to: (1) determine for first time if changes in CV structure/function occur as a result of exposure to WTC dusts: (2) ascertain if CV changes will be greater after WTC dust + DEP co-exposures relative to that due to DEP alone; and, (3) demonstrate that increases in CV changes associated with dust + DEP co-exposures will be related, in part, to increased lung retention of DEP. These innovative studies in rats, using relevant WTC dusts, DEP, and exposure scenarios, will allow us to: clarify what role these co-pollutants may have had in changes seen in the CV health of FR exposed in that initial 72 hr; obtain important biochemical/molecular clues to etiologies for the increasing CV problems seen in these FR; analyze the impact from exposure to WTC dusts on DEP retention and subsequent toxicities from the latter as they pertain to altered CV structures/functions; and, as a supplemental goal, potentially identify novel sero-markers of exposure-induced CV changes that could ultimately be used to identify sooner a presence of CV defects in still-outwardly healthy exposed FR. The studies address goals of the NIOSH: Cardiovascular Disease Cross-Sector Program, Public Safety Program (Priority 1: Reduce chronic illnesses among firefighters); and, FFFFIPP (Strategic Goal 1: Reduce CV deaths among firefighters), and will be in keeping with a major Research to Practice (r2p) initiative, i.e., to help reduce illness among FR/firefighters via NIOSH-generated knowledge, interventions, technologies.